Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.

• MeSH
• Antioxidants metabolism   MeSH
• Insulin-Secreting Cells metabolism   MeSH
• Humans MeSH
• Mitochondria * metabolism   MeSH
• Oxidation-Reduction * MeSH
• Oxidative Stress physiology   MeSH
• Signal Transduction physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH

SIGNIFICANCE: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.

• Keywords
• UCP2, anion transport, attenuation of superoxide formation, fatty acid cycling, mitochondrial uncoupling proteins, redox signaling,
• MeSH
• Antioxidants metabolism   MeSH
• Humans MeSH
• Mitochondrial Uncoupling Proteins metabolism   MeSH
• Oxidation-Reduction MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH
• Mitochondrial Uncoupling Proteins MeSH

Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

• Keywords
• adventitial fibroblasts, complex I, mitochondria, oxidative metabolism, pulmonary hypertension,
• MeSH
• Cell Respiration MeSH
• Chronic Disease MeSH
• Citric Acid Cycle MeSH
• Down-Regulation MeSH
• Energy Metabolism MeSH
• Phenotype MeSH
• Fibroblasts metabolism   MeSH
• Glycolysis MeSH
• Hypoxia complications   pathology   MeSH
• Pyruvic Acid metabolism   MeSH
• Humans MeSH
• Macrophages metabolism   MeSH
• Mitochondria metabolism   MeSH
• Oxidation-Reduction MeSH
• Oxidative Phosphorylation MeSH
• Paracrine Communication MeSH
• Lung pathology   MeSH
• Hypertension, Pulmonary complications   metabolism   pathology   MeSH
• Cellular Reprogramming * MeSH
• Pyruvate Dehydrogenase Complex metabolism   MeSH
• Electron Transport Complex I metabolism   MeSH
• Cattle MeSH
• Superoxides metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Pyruvic Acid MeSH
• Pyruvate Dehydrogenase Complex MeSH
• Electron Transport Complex I MeSH
• Superoxides MeSH

We reviewed mechanisms that determine reactive oxygen species (redox) homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release.

• MeSH
• Insulin-Secreting Cells metabolism   pathology   MeSH
• Homeostasis * MeSH
• Insulin metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Oxidation-Reduction MeSH
• Oxidative Stress MeSH
• Insulin Secretion MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Insulin MeSH

Reactive oxygen species (ROS) originating from mitochondria are perceived as a factor contributing to cell aging and means have been sought to attenuate ROS formation with the aim of extending the cell lifespan. Silybin and dehydrosilybin, two polyphenolic compounds, display a plethora of biological effects generally ascribed to their known antioxidant capacity. When investigating the cytoprotective effects of these two compounds in the primary cell cultures of neonatal rat cardiomyocytes, we noted the ability of dehydrosilybin to de-energize the cells by monitoring JC-1 fluorescence. Experiments evaluating oxygen consumption and membrane potential revealed that dehydrosilybin uncouples the respiration of isolated rat heart mitochondria albeit with a much lower potency than synthetic uncouplers. Furthermore, dehydrosilybin revealed a very high potency in suppressing ROS formation in isolated rat heart mitochondria with IC(50) = 0.15 μM. It is far more effective than its effect in a purely chemical system generating superoxide or in cells capable of oxidative burst, where the IC(50) for dehydrosilybin exceeds 50 μM. Dehydrosilybin also attenuated ROS formation caused by rotenone in the primary cultures of neonatal rat cardiomyocytes. We infer that the apparent uncoupler-like activity of dehydrosilybin is the basis of its ROS modulation effect in neonatal rat cardiomyocytes and leads us to propose a hypothesis on natural ischemia preconditioning by dietary polyphenols.

• MeSH
• Analysis of Variance MeSH
• Benzimidazoles MeSH
• Fluorescent Dyes MeSH
• Inhibitory Concentration 50 MeSH
• Carbocyanines MeSH
• Myocytes, Cardiac metabolism   MeSH
• Rats MeSH
• Mitochondria metabolism   MeSH
• Molecular Structure MeSH
• Rats, Wistar MeSH
• Reactive Oxygen Species metabolism   MeSH
• Rotenone toxicity   MeSH
• Silymarin chemistry   pharmacology   MeSH
• Oxygen Consumption drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine MeSH Browser
• Benzimidazoles MeSH
• dehydrosilybin MeSH Browser
• Fluorescent Dyes MeSH
• Carbocyanines MeSH
• Reactive Oxygen Species MeSH
• Rotenone MeSH
• Silymarin MeSH

Existing controversies led us to analyze absolute mRNA levels of mitochondrial uncoupling proteins (UCP1-UCP5). Individual UCP isoform mRNA levels varied by up to four orders of magnitude in rat and mouse tissues. UCP2 mRNA content was relatively high (0.4 to 0.8 pg per 10 ng of total mRNA) in rat spleen, rat and mouse lung, and rat heart. Levels of the same order of magnitude were found for UCP3 mRNA in rat and mouse skeletal muscle, for UCP4 and UCP5 mRNA in mouse brain, and for UCP2 and UCP5 mRNA in mouse white adipose tissue. Significant differences in pattern were found for rat vs. mouse tissues, such as the dominance of UCP3/UCP5 vs. UCP2 transcript in mouse heart and vice versa in rat heart; or UCP2 (UCP5) dominance in rat brain contrary to 10-fold higher UCP4 and UCP5 dominance in mouse brain. We predict high antioxidant/antiapoptotic UCP function in tissues with higher UCP mRNA content.

• MeSH
• DNA Primers genetics   MeSH
• Species Specificity MeSH
• Ion Channels metabolism   MeSH
• Rats MeSH
• Membrane Transport Proteins metabolism   MeSH
• RNA, Messenger metabolism   MeSH
• Mitochondrial Uncoupling Proteins MeSH
• Mitochondrial Proteins metabolism   MeSH
• Brain metabolism   MeSH
• Myocardium metabolism   MeSH
• Mice MeSH
• Lung metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Nerve Tissue Proteins metabolism   MeSH
• Spleen metabolism   MeSH
• Mitochondrial Membrane Transport Proteins MeSH
• Uncoupling Protein 2 MeSH
• Uncoupling Protein 3 MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• DNA Primers MeSH
• Ion Channels MeSH
• Membrane Transport Proteins MeSH
• RNA, Messenger MeSH
• Mitochondrial Uncoupling Proteins MeSH
• Mitochondrial Proteins MeSH
• Nerve Tissue Proteins MeSH
• Slc25a14 protein, rat MeSH Browser
• Slc25a27 protein, rat MeSH Browser
• Mitochondrial Membrane Transport Proteins MeSH
• Ucp2 protein, mouse MeSH Browser
• Ucp2 protein, rat MeSH Browser
• Ucp3 protein, mouse MeSH Browser
• Ucp3 protein, rat MeSH Browser
• Uncoupling Protein 2 MeSH
• Uncoupling Protein 3 MeSH